STUDY OF THE ADAMTS-13 LEVEL AS PREDICTIVE BIOMARKER FOR DEVELOPMENT OF PORTAL VEIN THROMBOSIS IN LIVER CIRRHOSIS
试验速览
- 阶段
- 不适用
- 发起方
- 入组人数
- 118
- 试验地点
- 1
- 主要终点
- Association of portal vein thrombosis with ADAMTS13 activity
研究概览
简要总结
Patients with cirrhosis of viral etiology (HCV/HBV); Patients with cirrhosis of any other etiology (alcohol, idiopatic, autoimmune). Planned Number of cirrhotic subjects 200 patients Inclusion Criteria Subjects (18 yr old) with liver cirrhosis of any etiology, Exclusion Criteria All patients should not have hepatocellular carcinoma or other malignant tumors, they should not be treated with anticoagulant / antiplatelet agents, not affected by PVT already diagnosed and not suffering from congenital coagulation disorders (haemophilia A / B, von disease Willebrand, another congenital deficiency of coagulation factors) or severe thrombocytopenia (<30,000 Plt / μL). Subject has participated in another clinical study within 30 days prior to study enrollment or is scheduled to participate in another clinical study on cirrhosis Primary Objective To describe the prospective modification of ADAMTS-13 level and other coagulation variables (e.g. FVIII, VWF:Ag/VWF:act) in cirrhotic patients during 18 months from the enrolment and to verify their predictive role as biomarker of development of portal vein thrombosis (PVT) Secondary Objectives To describe prospectively the modification of ADAMTS-13 level as a function of the etiology of cirrhosis Statistical analysis The total duration of the study will be of 12 months. The sample size of 200 subjects will be selected as a feasible number of patients to be recruited in a period of six months. The patients will be consecutively enrolled and followed for 18 months. As a result, in a follow up period of 18 months about 20-25 cases of PVT are expected. Continuous variables will be expressed as means ± standard deviations. In addition to descriptive statistics (location parameters), univariate analysis will be performed on each parameter and development of PVT during the follow up period. In previous observational studies both 1) a reduced PV flow [prospectively] and 2) a reduction of ADAMTS-13 are significantly associated with PVT. These associations will be investigated prospectively and analyzed simultaneously by a multivariate analysis and ROC curve to establish the sensitivity and specificity of these parameters as predictors of PVT development. Analyses will be performed using available data
详细描述
BACKGROUND AND JUSTIFICATION The occurrence of portal vein thrombosis (PVT) radically changes the prognosis of cirrhotic patients, particularly those awaiting liver transplantation. If this happens, it occurs in about 8-10% / year in patients with cirrhosis awaiting liver transplantation. Some studies have suggested the involvement of various risk factors for the development of PVT in cirrhotic patients, including the classic congenital and acquired thrombophilic conditions [1-6], although contributions of our research group have shown that a key element in the development of PVT in these patients is the decreased velocity of portal blood flow [7, 8]. The possible contribution of the von Willebrand factor (VWF) and ADAMTS-13, produced by the liver stellate cells [9], for the development of PVT is rather poorly documented. In a recent observational study of the proponent [10], conducted on 84 patients with liver cirrhosis, it was found that the level of circulating ADAMTS-13 is significantly lower in the group with PVT (median = 16.8% vs. 69.1%, p = 0.0047) and independently associated with the presence of portal thrombosis (p = 0.007). However, given the non-longitudinal nature of the study, it is possible that the decreased level of ADAMTS-13 observed is the consequence and not the cause of PVT. It is also yet to investigate the association of ADAMTS-13 level with the specific etiology of cirrhosis (viral, alcoholic, idiopathic, etc.) and the resulting inflammation during the course of the disease.
Duration of Study Period(s) and Subject Participation Two hundred (200) patients, consecutively enrolled in a period of about 6 months, will be followed for 18 months from the enrolment. As a result, in the subsequent 18 months about 20-25 cases of PVT will be expected. All patients will sign an informed consent. The severity of liver function failure will be assessed using the Child-Pugh score [11].
Primary Endpoint To describe in a prospective way the association of both basal ADAMTS-13 level and portal vein flow with development of PVT in cirrhotic patients during 18 months from the enrolment. Secondary Endpoints To describe prospectively the modification of ADAMTS-13 level as a function of the etiology of cirrhosis Coagulation and biochemical parameters
The prospective study will measure the following biochemical and coagulation parameters at each follow-up visit, scheduled at interval of 4 months according to routine controls:
Coagulation and thrombophilia factors All blood samples will be drawn under fasting conditions in the morning. Determinations of PT, APTT, fibrinogen, antithrombin, protein C, protein S, lupus anticoagulant, FVIII (two-stage chromogenic assay) and D-dimer will be carried out on an automatic coagulometer (ACL Top 700, IL). VWF-antigen VWF:activity will be measured in plasma samples by chemiluminescence assays. VWF multimer (VWFm) pattern was measured as previously reported [10]. FV Leiden R506Q and prothrombin G20210A genotyping of these polymorphisms was performed by using commercial kits based on PCR-RT-based method (from EliTechGroup S.p.A., Torino, Italy) on an automatic instrument (Model 7300, Applied Biosystem, Foster City, CA, USA).
研究设计
- 研究类型
- Observational
- 观察模型
- Case Only
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Inclusion criteria:
- •Patients with liver cirrhosis of any etiology, diagnosed using imaging and/or histological criteria and observed in the Liver Unit of the "A. Gemelli" University will be included in this study. All patients will sign an informed consent. The severity of liver function failure will be assessed using the Child-Pugh score [11]. Upper gastrointestinal endoscopy will be performed in all patients; the size of esophageal varices will be recorded as well as the presence of previous episodes of gastrointestinal bleeding. All the subjects will be outpatients and the time interval between the follow up visits will be approximately 120 days. The ultrasound criteria for the diagnosis of PVT will be the detection of echogenic material within one or more of the following vessels: portal trunk, right portal branch, left portal branch, splenic vein and superior mesenteric vein. Color and pulsed Doppler analysis will allow to confirm the diagnosis and to distinguish partial from complete obstructive thrombosis and in all cases the Doppler ultrasound diagnosis of PVT will be confirmed by contrast enhanced abdomen computed tomography. The presence and/or extension of the thrombosis to the other major vessels of the portal venous system (mesenteric or splenic vein) will registered in all patients. PVT will be classified according to the extension of thrombosis, as previously reported: grade I is referred to as portal thrombosis confined to the portal vein beyond the confluence of the splenic vein; grade II was a PVT extended to the superior mesenteric vein, but with patent mesenteric vessels; grade III is a PVT extended to the whole splanchnic venous system, but with large collaterals; grade IV is a thrombosis extended to the whole splanchnic venous system with only fine collaterals [12]. All the biochemical and coagulation parameters described below, including ADAMTS-13 and VWF levels, will be measured at each follow up visit.
排除标准
- •Exclusion Criteria All patients should not have hepatocellular carcinoma or other malignant tumors, they should not be treated with anticoagulant / antiplatelet agents, not affected by PVT already diagnosed and not suffering from congenital coagulation disorders (haemophilia A / B, von disease Willebrand, another congenital deficiency of coagulation factors) or severe thrombocytopenia (<30,000/µl).
结局指标
主要结局
Association of portal vein thrombosis with ADAMTS13 activity
时间窗: 18 months
Primary Endpoint To describe in a prospective way the association of both basal ADAMTS-13 level and portal vein flow with development of PVT in cirrhotic patients during 18 months from the enrolment. Measurement of ADAMTS-13 activity. ADAMTS-13 activity was measured in citrated plasma samples by a fluorescence resonance energy transfer (FRET)-based assay,
次要结局
- Analysis of ADAMTS-13 and VWF levels as a function of the etiology of cirrhosis.(18 months)
研究者
Raimondo De Cristofaro
Prof. Raimondo De Cristofaro, MD
Catholic University of the Sacred Heart